# Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2022 · $422,101

## Abstract

Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from hepatic steatosis to
steatohepatitis with varying degrees of fibrosis and cirrhosis. ALD is a major cause of morbidity, mortality, and
health care costs in the US and worldwide. However, there is no FDA-approved therapy for any stage of ALD.
There is also an incomplete understanding of the mechanisms and mediators of disease progression and
severity. Soluble epoxide hydrolase (s-EH), a master enzyme that regulates the metabolism of endogenous
bioactive lipids (e.g., epoxy-fatty acids, Ep-FAs), has recently been recognized as an emerging therapeutic target
in multiple diseases. The overall goal of this project is to test the therapeutic efficacy of s-EH inhibition at
different stages of ALD severity, and to provide a mechanistic foundation for using s-EH inhibition as a novel
therapy for alcohol-induced liver pathology. Aim 1. To test the therapeutic effectiveness of s-EH inhibition
as a novel therapeutic strategy for ALD. We will: i) test whether modulation of s-EH activity by pharmacological
inhibition or s-EH (Ephx2) genetic ablation can effectively attenuate or prevent EtOH-induced liver injury in
experimental ALD; ii) evaluate whether s-EH inhibition leads to stabilization of blood and liver Ep-FAs; and iii)
correlate changes in Ep-FA levels with markers of liver injury. Systemic and targeted liver-specific delivery of s-
EH inhibitors (t-TUCB and TPPU), and WT and Ephx2 -/- mice (global and liver-specific) will be used in multiple
animal models of ALD, which produce different stages of disease severity and which recapitulate different
features of human ALD. This allows for a rigorous evaluation of the effects of s-EH inhibition at different stages
of ALD severity. Treatment and prevention paradigms will be applied. Aim 2. To explore mechanism(s)
underlying the beneficial effects of s-EH inhibition in experimental ALD. We will determine whether Ep-FA
stabilization mediated by s-EH inhibition plays a critical role in attenuation of EtOH-induced liver injury. We will
test whether n3 vs n6 Ep-FAs exert a greater beneficial effect by enhancing M2 macrophage polarization,
increasing a pro-restorative/pro-resolving macrophage phenotype, and by Ep-FAs-PPARγ-CXCL1-mediated
reduction of neutrophil infiltration. s-EH inhibitors, WT, transgenic fat-1 mice (which endogenously convert n6
PUFAs to n3 PUFAs), and hepatocyte-specific Pparγ-/- mice will be used. In vivo and in vitro studies will be
performed. Aim 3. To evaluate EtOH-induced alterations in s-EH and Ep-FAs in human ALD. Utilizing de-
identified human plasma and whole blood samples, we will: i) evaluate alterations in plasma Ep-FAs and
establish relationships between biomarkers of liver injury and systemic inflammation in patients with alcohol-
associated hepatitis (AH); ii) determine the effects of n3-PUFA dietary supplementation on plasma Ep-FAs in
heavy drinking individuals; and iii) test whether s-EH inhibit...

## Key facts

- **NIH application ID:** 10389013
- **Project number:** 1R01AA028905-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Irina A. Kirpich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $422,101
- **Award type:** 1
- **Project period:** 2022-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389013

## Citation

> US National Institutes of Health, RePORTER application 10389013, Role of Soluble Epoxide Hydrolase in Alcohol-Associated Liver Disease (1R01AA028905-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10389013. Licensed CC0.

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